Identification of the components, targets, and magnitude of an effective immune response to HIV are important steps toward the development of effective vaccines or immunotherapies. Although patients with normal CD4+ T cell counts and low levels of plasma virus are a heterogeneous group, a small subgroup of patients with truly non-progressive HIV infection and restriction of virus replication likely hold important clues to the basis of an effective immune response to HIV. A small subpopulation (fewer than 0.8% of HIV infected individuals) shows no signs of progression over a 10-year period. We have assembled a unique cohort of such patients with non-progressive disease termed long-term nonprogressors (LTNP). Many of these patients have been infected for 20 years in the absence of antiretroviral therapy with no CD4+ T cell decline, and plasma viral RNA below 50 copies per milliliter. Cells from these patients are being used to systematically dissect the mechanisms of immune mediated restriction of virus replication. HIV-specific T cell responses of these patients have been studied in extreme detail. Prior work has indicated that there is a dramatic association with the HLA B*5701 allele and that the immune response is highly focused on peptides restricted by this allele. More recently we have found that this focus is specific to HIV, and is not found in the response to other pathogens such as Hepatitis C virus or Cytomegalovirus. LTNP patients do not differ in the frequency of HIV-specific T cells nor ability to recognize the autologous virus when compared to progressors. Thus far the only difference in the HIV-specific immune response that distinguishes LTNP is the maintenance of HIV-specific CD8+ T cells with a high proliferative capacity compared to progressors. This proliferation is coupled to or parallels perforin expression. Strong HIV specific CD4+ T cell proliferative responses are demonstrable in these LTNP patients. However, they are not demonstrable in the majority of infected patients with progressive disease. It has been presumed that HIV-specific CD4+ T cells are killed upon encountering antigen and maintenance of CD4+ T cell responses in some patients causes the restriction of virus replication. We have recently shown that although proliferative responses were absent in patients with poorly restricted virus replication, HIV-specific CD4+ T cells capable of proliferation and interleukin-2 (IL-2) production are maintained in patients on effective antiretroviral therapy. Diminished proliferation and IL-2 production are an effect, and not a cause, of high levels of viral replication. We used 11-color flow cytometry to compare the frequency, phenotype, and cytokine secretion of HIV-specific CD4+ T cells to those specific for tetanus, influenza, CMV, Epstein-Barr virus, and Adenovirus in LTNP and progressor cohorts. The frequency, phenotype and function of HIV-specific CD4+ T cells were similar to those specific for these other pathogens. Taken together, we do not detect differences in the HIV-specific CD4+ T cells between patients with or without immunologic control of HIV that would suggest a critical defect in this response. These findings raise a number of fundamental issues for the potential use of the T cell response to HIV in prophylactic vaccines or immunotherapies. Because most individuals fail to restrict HIV replication despite a broad, high frequency CD8+ T cell response, simply stimulating a high frequency response via a therapeutic or prophylactic vaccine will not necessarily result in durable immunologic control. Thus, it is unclear whether CD8+ T cells can be sufficiently primed such that qualitative changes in the CD8+ T cell response can be avoided. In addition, it is unclear how long after HIV infection of vaccinees these qualitative changes might occur and immunologic restriction of viral replication is lost. Further, it is unclear whether these qualitative changes can be reversed in infected individuals. A deeper understanding of the basis of immunologic control in LTNP and the loss of immunologic control in progressors is likely to provide information that is critical for use of the cellular immune response in each of these settings.